Fcγ-receptors Induce Mac-1 (CD11b/CD18) Mobilization and Accumulation in the Phagocytic Cup for Optimal Phagocytosis

Functional interactions between Fcγ-receptors (FcγR) and the β2 integrin Mac-1 (CD11b/CD18) have been described, but the molecular basis of this relationship remains unclear. Although the glycosylphosphatidylinositol-linked receptor FcγRIIIB of human neutrophils is constitutively associated with Mac-1, we found no evidence for direct physical association between Mac-1 and the FcγR of mouse macrophages, which are transmembrane proteins. Nevertheless, Mac-1 accumulated in the phagocytic cup following engagement of FcγR by IgG-opsonized particles. Blocking the CD18 chains of β2 integrins by using specific antibodies reduced Mac-1 accumulation in the cup. These antibodies or the addition of the recombinant CD11b I-domain inhibited the ingestion of IgG-opsonized particles. FcγR cross-linking stimulated cell adhesion to surfaces coated with Mac-1 ligands and in addition enabled macrophages to bind C3bi-opsonized particles, indicating that FcγR-derived signals induce activation of Mac-1. Measurements of fluorescence recovery after photobleaching revealed that whereas most (>80%) of Mac-1 is immobile in resting cells, stimulation of FcγR markedly increases the mobile fraction of the integrin. Activation of Mac-1 by FcγR required the activity of Src family tyrosine kinases, phosphatidylinositol 3-kinase and phospholipase C, with the release of diacylglycerol and stimulation of protein kinase C. Because elevated cytosolic Ca2+ was not required, we suggest that novel protein kinase C isoforms are involved in Mac-1 activation. These results suggest that FcγR stimulation promotes Mac-1 clustering into high avidity complexes in phagocytic cups by releasing the integrin from cytoskeletal constraints and enhancing its lateral diffusion. FcγR can enhance host defense by activating Mac-1 (and possibly other integrins), having a synergistic effect on pathogen engulfment and promoting the adherence of phagocytes at sites of infection. Functional interactions between Fcγ-receptors (FcγR) and the β2 integrin Mac-1 (CD11b/CD18) have been described, but the molecular basis of this relationship remains unclear. Although the glycosylphosphatidylinositol-linked receptor FcγRIIIB of human neutrophils is constitutively associated with Mac-1, we found no evidence for direct physical association between Mac-1 and the FcγR of mouse macrophages, which are transmembrane proteins. Nevertheless, Mac-1 accumulated in the phagocytic cup following engagement of FcγR by IgG-opsonized particles. Blocking the CD18 chains of β2 integrins by using specific antibodies reduced Mac-1 accumulation in the cup. These antibodies or the addition of the recombinant CD11b I-domain inhibited the ingestion of IgG-opsonized particles. FcγR cross-linking stimulated cell adhesion to surfaces coated with Mac-1 ligands and in addition enabled macrophages to bind C3bi-opsonized particles, indicating that FcγR-derived signals induce activation of Mac-1. Measurements of fluorescence recovery after photobleaching revealed that whereas most (>80%) of Mac-1 is immobile in resting cells, stimulation of FcγR markedly increases the mobile fraction of the integrin. Activation of Mac-1 by FcγR required the activity of Src family tyrosine kinases, phosphatidylinositol 3-kinase and phospholipase C, with the release of diacylglycerol and stimulation of protein kinase C. Because elevated cytosolic Ca2+ was not required, we suggest that novel protein kinase C isoforms are involved in Mac-1 activation. These results suggest that FcγR stimulation promotes Mac-1 clustering into high avidity complexes in phagocytic cups by releasing the integrin from cytoskeletal constraints and enhancing its lateral diffusion. FcγR can enhance host defense by activating Mac-1 (and possibly other integrins), having a synergistic effect on pathogen engulfment and promoting the adherence of phagocytes at sites of infection. Mac-1, a heterodimeric receptor primarily expressed in neutrophils and monocytes/macrophages, is composed of a specific α chain (CD11b) and the β2 chain (CD18) which is common to the other members of the β2 integrin family (1Ehlers M.R. Microbes Infect. 2000; 2: 289-294Crossref PubMed Scopus (258) Google Scholar). As is the case for other integrins, Mac-1 (also known as CD11b/CD18, αMβ2, Mo-1, or CR3) activation is required for efficient binding to several ligands such as intercellular adhesion molecule 1, C3bi, or fibrinogen. Activation of the cells by specific agonists induces the receptor to undergo conformational changes, mobilization, and clustering by a process known as inside-out signaling (2Hughes P.E. Pfaff M. Trends Cell Biol. 1998; 8: 359-364Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 3van Kooyk Y. Figdor C.G. Curr. Opin. Cell Biol. 2000; 12: 542-547Crossref PubMed Scopus (294) Google Scholar). A variety of studies have demonstrated that Mac-1 participates in a number of important aspects of the innate immune response, including phagocyte adhesion, migration, and engulfment of complement-opsonized particles (1Ehlers M.R. Microbes Infect. 2000; 2: 289-294Crossref PubMed Scopus (258) Google Scholar, 4Coxon A. Rieu P. Barkalow F.J. Askari S. Sharpe A.H. von Andrian U.H. Arnaout M.A. Mayadas T.N. Immunity. 1996; 5: 653-666Abstract Full Text PDF PubMed Scopus (546) Google Scholar). Such functions are generally triggered by direct binding of ligands like intercellular adhesion molecule 1 and C3 complement fragment C3bi to Mac-1. In addition, Mac-1 interacts with and appears to serve as a signaling partner for glycosylphosphatidylinositollinked receptors such as urokinase-type plasminogen activator receptor and CD14 (5Todd III, R.F. Petty H.R. J. Lab. Clin. Med. 1997; 129: 492-498Abstract Full Text PDF PubMed Scopus (93) Google Scholar). Whereas Mac-1 can directly recognize components of the microbial wall (6Vetvicka V. Thornton B.P. Ross G.D. J. Clin. Investig. 1996; 98: 50-61Crossref PubMed Scopus (362) Google Scholar, 7Thornton B.P. Vetvicka V. Pitman M. Goldman R.C. Ross G.D. J. Immunol. 1996; 156: 1235-1246PubMed Google Scholar), phagocytosis via this receptor is most efficient when the target particles are coated with complement fragment C3bi, a process known as opsonization. Opsonic phagocytosis can also be mediated by Fcγ-receptors (FcγR), 1The abbreviations used are: FcγR, Fcγ-receptors; agg-IgG, aggregated human IgG; FCS, fetal calf serum; FRAP, fluorescence recovery after photobleaching; HBSS, Hank's buffered saline solution; HPMI, Hepes-buffered solution RPMI-1640; IgG-RBC or C3bi-RBC, IgG-or C3bi-opsonized red blood cells; mAb, monoclonal antibodies; MFI, mean fluorescence intensity; PI3K, phosphatidylinositol 3-kinase; FITC, fluorescein isothiocyanate; PMA, phorbol 12-myristate 13-acetate; Ab, antibody; BSA, bovine serum albumin; PE, phycoerythrin; PBS, phosphate-buffered saline; PKC, protein kinase C; TRITC, tetramethylrhodamine isothiocyanate; GST, glutathione S-transferase; GFP, green fluorescent protein; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester; DiC8, 1,2-dioctanoyl-sn-glycerol; PLC, phospholipase C. which recognize the constant region of IgG bound to antigenic particles (8Gessner J.E. Heiken H. Tamm A. Schmidt R.E. Ann. Hematol. 1998; 76: 231-248Crossref PubMed Scopus (345) Google Scholar). Unlike the integrins, however, FcγR are capable of binding and responding to their ligands without priming, i.e. stimulation of the cells by other agonists. In vitro studies using single opsonins have demonstrated that engagement of either FcγR or Mac-1 suffices to initiate phagocytosis. However, interactions between the two systems have been suggested by various observations. Neutrophils from leukocyte adhesion deficiency which have in the CD18 A. PubMed Google Scholar), have a reduced to IgG-opsonized red blood cells J. Clin. Investig. PubMed Scopus Google Scholar). antibodies that Mac-1 phagocytosis without the binding of FcγR to its ligands J. Immunol. Google Scholar). adhesion of neutrophils to immune complexes was inhibited by antibodies either CD18 or CD11b J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, S. H. S. M. H. J. Biol. PubMed Scopus Google Scholar), and immune of neutrophils in or on immune complexes in vitro A. Mayadas T.N. J. Med. 1997; PubMed Scopus Google Scholar). These studies and that of A. S. S. Mayadas T.N. Immunity. Full Text Full Text PDF PubMed Scopus Google suggest that Mac-1 is required for leukocyte adhesion following FcγR FcγR and Mac-1 receptors remains of FcγR, the human been to in physical association with Mac-1. A is to between which undergo in human neutrophils M. III, R.F. Petty H.R. J. Immunol. Google Scholar, H. III, R.F. Petty H.R. J. Biol. Google Scholar). However, association with FcγRIIIB is to for the of FcγRIIIB is to human neutrophils J. Med. PubMed Scopus Google Scholar, M. J. Med. 1996; PubMed Scopus Google Scholar), between Mac-1 and FcγR been in cell that this receptor is clustering and signaling be by the of Mac-1 and which is a glycosylphosphatidylinositol-linked and of In this we to the transmembrane of FcγR, such as expressed in cells undergo interactions with Mac-1. this we the of Mac-1 in the phagocytosis of IgG-RBC in mouse In we direct physical interactions between Mac-1 and FcγR in cells, and we the that FcγR engagement to inside-out activation of Mac-1. and fetal calf serum from and IgG from and was from the to was by of the and in the the α I-domain to are by of the recombinant was as J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). CD18 and and from the and and from and from H. and A. of or from the IgG fraction from by using to the and and IgG from and IgG and or from and C from and or from and from other from human IgG was by human IgG to for by at for was used at Cell and macrophages in with and and 1 the immune binding cells on by with for at with and to at for in Hepes-buffered receptor cells on with the S. Clin. Immunol. 98: PubMed Scopus Google Scholar), a from A. using to the and used of and with IgG as M. A. S. J. Cell Biol. 2000; PubMed Scopus Google Scholar). C3bi was by with of in with and for 1 at was and with serum for at with and used for binding induce cells to IgG-opsonized in with at for to by for by with to with or with at for IgG-RBC binding cells to IgG-opsonized the as for phagocytosis that was for at by at with to with binding cells for and with or without or of for to the addition of the cells with or C at by in to addition of with the cells for and with the cells stimulated with Blocking and for at with to binding cells for at with or without or IgG in with IgG to the and binding or phagocytosis in the of the Ab, as CD18 the was with IgG-RBC to with by for 1 accumulation of CD18 in the cup and was from by the in the cup and in by using using the recombinant or GST, IgG-RBC for with or without recombinant protein in BSA, and this was to cells to was as and cells with 1 of of or of as to and with or without for at or as at was to the in PBS, and with to human IgG and cells from and with in for at in the case of at in the of and with buffered saline solution and to with for and at for with or the cells for of human IgG or integrin chains with and the number of integrin the fluorescence PE, was used to the with of and of by a with and the number of cell of β2 integrins, cells with activation a from at for using or mouse in with and with or without in HBSS, 1 and of IgG used as after of integrins and receptors was using on either with or to 1 for at cells and the of was of in using the of the of the in a of the fluorescence A from the that was to serve as a after photobleaching with a to photobleaching for a to and in as and to the at to for or for in recovery of the of CD11b or was as the of the fluorescence to the to recovery was also of the cells and after photobleaching and to that no or in the of and as A. Mayadas T.N. J. Med. 1997; PubMed Scopus Google Scholar). coated with and with for and coated with for and with for immune with IgG in for 1 cells in or and for at with and with to integrins or by and cells with and with in at or for at was by with in for for 1 with in with and was for 1 at in for 1 at with by and fluorescence using a with a FITC, and using the and expressed as mean to the of using CD18 for of the and the of CD18 and CD11b on the of cells by of CD18 of CD18 and CD11b was which is to for macrophages G.D. J. Biol. PubMed Scopus Google Scholar). These that in cells of the CD18 chains associated with CD11b chains to the Mac-1 integrin a between β2 integrins and transmembrane FcγR, we the effect of monoclonal antibodies CD18 J. Med. PubMed Scopus Google on the phagocytosis of IgG-RBC by 1 that with of the phagocytosis phagocytic from in the to in cells effect was a of no of phagocytosis of phagocytosis by was not to with the binding of the opsonins to the FcγR, of the number of IgG-RBC associated with the phagocytes revealed no between and cells 1, Although we no of the α chain of Mac-1, we that this receptor have been at in for the of on its and on the of J. Immunol. Google Scholar), found that Mac-1 is the β2 integrin to phagocytosis in human and A of of the of known as the been in the binding of Mac-1 to several ligands J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Mac-1 is required for phagocytosis of we the effect of a recombinant protein of the I-domain of CD11b on phagocytosis. by using the protein 1 that in the of the the phagocytic was reduced by as with whereas in the of no effect on phagocytosis. These results that is in at in the I-domain of In addition to CD11b/CD18, we found that cells also the of this β2 integrin phagocytosis. of the α chain of not phagocytosis of IgG-RBC These results that not β2 integrin family members in phagocytosis. on CD18 and CD11b the of this of CD18 and CD11b at the the relationship between FcγR and Mac-1, we the of CD18 and CD11b phagocytosis of that CD18 and CD11b in phagocytic by the of IgG-RBC by the in a case of CD18 accumulation in the cup and the used to the in CD18 and CD11b at the in to its in the In the of CD18 at the cup the found in other of the the These results are with the of Mac-1 J. A. V. J. Cell PubMed Google in macrophages phagocytosis of FcγR and CD11b FcγR are known to at the phagocytic the accumulation of Mac-1 that the two of receptors the two receptor are constitutively we of FcγR by IgG complexes also the of Mac-1. at to the of cells, which can be by A and or by using the receptor clustering triggered by induces of the FcγR, which can be by and and by using antibodies to human IgG or FcγR A. S. J. PubMed Scopus Google for that whereas a fraction of FcγR the of Mac-1 at the cell was by and with and but by C and with and results when was by cross-linking FcγR by using mouse IgG and IgG These suggest that Mac-1 and FcγR are not constitutively Nevertheless, is that constitutively associated receptors undergo and that Mac-1 to the used to the of the which not receptor was by the lateral of Mac-1 and of FcγR by using fluorescence recovery after photobleaching on the the of the cells, for to the and that the was the As in and in and the of FcγR was mobile in the of the a fraction of Mac-1 was and the of lateral of mobile receptors was and that of These results are in with the of Mac-1 been to be by its with the J. Immunol. 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